scholarly journals The STI1‐domain is a flexible alpha‐helical fold with a hydrophobic groove

2021 ◽  
Vol 30 (4) ◽  
pp. 882-898
Author(s):  
Michelle Y. Fry ◽  
Shyam M. Saladi ◽  
William M. Clemons
Keyword(s):  
Hydrophobic Groove

scholarly journals Structural insights into ubiquitin recognition and Ufd1 interaction of Npl4

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yusuke Sato ◽  
Hikaru Tsuchiya ◽  
Atsushi Yamagata ◽  
Kei Okatsu ◽  
Keiji Tanaka ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Mutational Analysis ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Binding Motif ◽  
Polyubiquitin Chain ◽  
Hydrophobic Groove ◽  
Terminal Loop ◽  
Initial Binding ◽  
Structural Insights

AbstractNpl4 is likely to be the most upstream factor recognizing Lys48-linked polyubiquitylated substrates in the proteasomal degradation pathway in yeast. Along with Ufd1, Npl4 forms a heterodimer (UN), and functions as a cofactor for the Cdc48 ATPase. Here, we report the crystal structures of yeast Npl4 in complex with Lys48-linked diubiquitin and with the Npl4-binding motif of Ufd1. The distal and proximal ubiquitin moieties of Lys48-linked diubiquitin primarily interact with the C-terminal helix and N-terminal loop of the Npl4 C-terminal domain (CTD), respectively. Mutational analysis suggests that the CTD contributes to linkage selectivity and initial binding of ubiquitin chains. Ufd1 occupies a hydrophobic groove of the Mpr1/Pad1 N-terminal (MPN) domain of Npl4, which corresponds to the catalytic groove of the MPN domain of JAB1/MPN/Mov34 metalloenzyme (JAMM)-family deubiquitylating enzyme. This study provides important structural insights into the polyubiquitin chain recognition by the Cdc48–UN complex and its assembly.

scholarly journals Conserved Mode of Interaction between Yeast Bro1 Family V Domains and YP(X) n L Motif-Containing Target Proteins

2015 ◽  
Vol 14 (10) ◽  
pp. 976-982 ◽  
Author(s):  
Yoko Kimura ◽  
Mirai Tanigawa ◽  
Junko Kawawaki ◽  
Kenji Takagi ◽  
Tsunehiro Mizushima ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Mammalian Cells ◽  
Tyrosine Phosphatase ◽  
Binding Specificity ◽  
Target Protein ◽  
Target Proteins ◽  
Protein Tyrosine ◽  
Hydrophobic Groove ◽  
Domain Protein ◽  
Common Architecture

ABSTRACT Yeast Bro1 and Rim20 belong to a family of proteins which possess a common architecture of Bro1 and V domains. Alix and His domain protein tyrosine phosphatase (HD-PTP), mammalian Bro1 family proteins, bind YP(X) n L ( n = 1 to 3) motifs in their target proteins through their V domains. In Alix, the Phe residue, which is located in the hydrophobic groove of the V domain, is critical for binding to the YP(X) n L motif. Although the overall sequences are not highly conserved between mammalian and yeast V domains, we show that the conserved Phe residue in the yeast Bro1 V domain is important for binding to its YP(X) n L-containing target protein, Rfu1. Furthermore, we show that Rim20 binds to its target protein Rim101 through the interaction between the V domain of Rim20 and the YPIKL motif of Rim101. The mutation of either the critical Phe residue in the Rim20 V domain or the YPIKL motif of Rim101 affected the Rim20-mediated processing of Rim101. These results suggest that the interactions between V domains and YP(X) n L motif-containing proteins are conserved from yeast to mammalian cells. Moreover, the specificities of each V domain to their target protein suggest that unidentified elements determine the binding specificity.

scholarly journals Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49601 ◽  
Author(s):  
Abul Azad ◽  
Joanna Fox ◽  
Sabrina Leverrier ◽  
Alan Storey
Keyword(s):  
Hydrophobic Groove

Monovalent mannose-based DC-SIGN antagonists: Targeting the hydrophobic groove of the receptor

2014 ◽  
Vol 75 ◽  
pp. 308-326 ◽  
Author(s):  
Tihomir Tomašić ◽  
David Hajšek ◽  
Urban Švajger ◽  
Jernej Luzar ◽  
Nataša Obermajer ◽  
...  
Keyword(s):  
Hydrophobic Groove

scholarly journals A novel computational method to design BH3-mimetic peptide inhibitors that can bind specifically to Mcl-1 or Bcl-XL

2020 ◽  
Author(s):  
C. Narendra Reddy ◽  
Nishat Manzar ◽  
Bushra Ateeq ◽  
Ramasubbu Sankararamakrishnan
Keyword(s):  
B Cell Lymphoma ◽  
High Specificity ◽  
Computational Method ◽  
Interaction Energies ◽  
Wild Type ◽  
Hydrophobic Groove ◽  
Binding Interface ◽  
Bh3 Domain ◽  
Anti Cancer ◽  
Charged Residues

AbstractInteractions between pro- and anti-apoptotic B cell lymphoma 2 (Bcl-2) proteins decide the fate of the cell. BH3 (Bcl-2 homology 3) domain of pro-apoptotic Bcl-2 proteins interacts with the exposed hydrophobic groove of anti-apoptotic counterparts. Design and development of BH3 mimetics that target the hydrophobic groove of specific anti-apoptotic Bcl-2 proteins have the potential to become anti-cancer drugs. We have developed a novel computational method to design sequences with BH3 domain features that can bind specifically to anti-apoptotic Mcl-1 or Bcl-XL. In this method, we retained the four highly conserved hydrophobic and aspartic residues of wild-type BH3 sequences and randomly substituted all other positions to generate a large number of BH3-like sequences. We modeled 20000 complex structures with Mcl-1 or Bcl-XL using the BH3-like sequences derived from five wild-type pro-apoptotic BH3 peptides. Peptide-protein interaction energies calculated from these models for each set of BH3-like sequences resulted in negatively-skewed extreme value distributions. The selected BH3-like sequences from the extreme negative tail regions have distinctly different distribution of charged residues for Mcl-1 and Bcl-XL. BH3-like sequences with highly favorable interaction energies prefer to have acidic residues for Mcl-1 and are enriched with basic residues when they bind to Bcl-XL. With the charged residues often away from the binding interface, the overall electric field generated by the charged residues result in highly favorable long-range electrostatic interaction energies between the peptide and the protein giving rise to high specificity. Cell viability studies of representative BH3-like peptides further validated the predicted specificity.

scholarly journals Crystal structures of Bax and Bak Reveal Molecular Events Initiating Apoptosis

2014 ◽  
Vol 70 (a1) ◽  
pp. C1490-C1490
Author(s):  
Peter Czabotar ◽  
Jason Brouwer ◽  
Dana Westphal ◽  
Geoff Thompson ◽  
Peter Colman
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Structural Studies ◽  
Core Domain ◽  
Hydrophobic Groove ◽  
Outer Leaflet ◽  
Molecular Events ◽  
Surface Crystal

A key event in apoptosis is the conversion of Bax or Bak from inert monomers into cytotoxic mitochondrial membrane perforating oligomers. Certain BH3-only relatives can initiate this step through direct interactions, yet the means by which conformational changes are invoked, the nature of the conformational changes themselves, the mechanism by which they insert into membranes and the process by which they perforate these barriers has largely remained a mystery. Our recent structural studies provided the first insights into this process for Bax [1]. We found that BH3 domains activate Bax by binding to a hydrophobic groove on its surface. Crystal structures of these complexes revealed an unexpected conformational change involving dissociation of a previously unrecognized "core" domain from a "latch' domain. A further structure of the freed Bax "core" domains revealed that these form dimers that possess a surface of aromatic residues which we hypothesis engage the outer leaflet of the mitochondrial membrane and induce curvature. We have now extended our studies to include structures of Bax bound to alternative BH3-only proteins providing new insights into key interactions occurring at this interface. Additionally, we have solved structures of activated Bak and of the freed Bak "core" domain dimers. These results further our understanding of the molecular mechanisms by which these highly dynamic proteins engage the mitochondrial membrane and thus control the life/death switch in cells.

scholarly journals Mechanisms of CP190 Interaction with Architectural Proteins in Drosophila Melanogaster

2021 ◽  
Vol 22 (22) ◽  
pp. 12400
Author(s):  
Marat Sabirov ◽  
Anastasia Popovich ◽  
Konstantin Boyko ◽  
Alena Nikolaeva ◽  
Olga Kyrchanova ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Transcriptional Repressors ◽  
Protein Protein Interactions ◽  
Yeast Two Hybrid ◽  
Btb Domain ◽  
Hydrophobic Groove ◽  
Architectural Proteins ◽  
Two Hybrid ◽  
Human Bcl6 ◽  
Unstructured Regions

Most of the known Drosophila architectural proteins interact with an important cofactor, CP190, that contains three domains (BTB, M, and D) that are involved in protein–protein interactions. The highly conserved N-terminal CP190 BTB domain forms a stable homodimer that interacts with unstructured regions in the three best-characterized architectural proteins: dCTCF, Su(Hw), and Pita. Here, we identified two new CP190 partners, CG4730 and CG31365, that interact with the BTB domain. The CP190 BTB resembles the previously characterized human BCL6 BTB domain, which uses its hydrophobic groove to specifically associate with unstructured regions of several transcriptional repressors. Using GST pull-down and yeast two-hybrid assays, we demonstrated that mutations in the hydrophobic groove strongly affect the affinity of CP190 BTB for the architectural proteins. In the yeast two-hybrid assay, we found that architectural proteins use various mechanisms to improve the efficiency of interaction with CP190. Pita and Su(Hw) have two unstructured regions that appear to simultaneously interact with hydrophobic grooves in the BTB dimer. In dCTCF and CG31365, two adjacent regions interact simultaneously with the hydrophobic groove of the BTB and the M domain of CP190. Finally, CG4730 interacts with the BTB, M, and D domains of CP190 simultaneously. These results suggest that architectural proteins use different mechanisms to increase the efficiency of interaction with CP190.

scholarly journals The client-binding domain of the cochaperone Sgt2 has a helical-hand structure that binds a short hydrophobic helix

2019 ◽  
Author(s):  
Ku-Feng Lin ◽  
Michelle Y. Fry ◽  
Shyam M. Saladi ◽  
William M. Clemons
Keyword(s):  
Membrane Proteins ◽  
Molecular Model ◽  
Minimal Length ◽  
Terminal Region ◽  
Integral Membrane Proteins ◽  
Human Homolog ◽  
Cellular Homeostasis ◽  
Fungal Protein ◽  
Hydrophobic Groove ◽  
Hydrophobic Helix

AbstractThe targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2 binding to TA IMP clients. We establish that the Sgt2 C-terminal region is flexible but conserved and sufficient for client binding. A molecular model for this domain reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA IMP clients with hydrophobic faces and a minimal length of 11 residues. This work places Sgt2 into a broader family of TPR-containing co-chaperone proteins.

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